14. Fibrous Proteins

Secondary Structures

Dominant motif of fibrous proteins

What is the most abundant protein in mammals?

Collagen

What is the major stress bearing component in the connective tissue?

Collagen

Fibroblasts

synthetize the majority of the collagen

Collagen type 1

Component of most connective tissue, including bone

Primary structure of collagen

Characterized by the presence of Glycine (Gly, G) every third residue.

Gly-X-Y, what is x?

Usually proline (10%)

Gly-X-Y, what is Y?

Usually hydroxylysine and hydroxyproline (10%)

Secondary structure of collagen

Right handed superhelix

Right handed superhelix

A triple helical structure of three α-chains twisted together

α-chain

Left-handed helix formed by each polypeptide with three residues per turn. A combination of three of these chains characterize the type of collagen.

How can three α-chains twist together without interference of a side chain?

The presence of Gly every three residues allows for close approximation without interference.

Proline and Hydrogen bonds

Stabilize the right handed super helix

Hydroxilation of Pro and Lys residues

Very specific rxn for Pro and Lys that occurs inside a collagen molecule. Formation of a hydroxyl group.

Prolyl or lysyl hydroxylase

Enzime that catabolizes the hydroxilation of Pro and Lys

Hydroxyprolation in the fourth carbon

occurs when proline is in the Y position (Gly-X-Y)

Hydroxyprolation in the third carbon

Occurs when proline is in the X postion (Gly-X-Y)

Hydroxylation in the fifth carbon

Occurs when lysine is in the Y position (Gly-X-Y)

Scurvy

A disease caused by deficiencies in hydroxylation which result in defective synthesis of collagen and deficiency of abscorbic acid (vit c)

Glycosilation of Hydroxylysine (Hyl)

Covalent binding of galactose or glucose-galactose disaccharide to the hydroxyl group of Hyl.

Galactosyl transferase and glucosyl transferase

Enzimes that catabolize glycosilation of hydroxylysine.

Synthetic Amino acids

Those that can't be synthesized by the body.

Strength of collagen fibrils

Strengthened by the crosslinking of lysine and hydroxylisine residues.

Osteogenesis Imperfecta

Brittle bone syndrome. Caused by mutations in the collagen genes that prevent stable triple helix formation and leads to unfolding of the protein at body temp.

Ehlers-Danlos syndrome

Inherited disorder of connective tissue due to defects in the collagen molecule.

Elastin

Connective tissue protein responsible for properties of extensibility and elastic recoil in tissues. One genetic type.

Fibroblasts

synthesize elastin as a soluble monomer called tropoelastin.

Amino Acid composition of elastin

Abundant in nonpolar small aa (Gly, Ala, Val). Rich in Pro and Lys. Some Hyp, but no Hyl.

Random Coil

Secondary structure of elastin

Elastin cross-link

Unique crosslink of up to four lysine residues. Three of the residues is converted into allysine. Highly insoluble and very stable.

Desmosine crosslink

Produced by condensation of the three allysine residues with an unmodified Lys.

Elastaste

enzyme that is secreted by neutrophils and degrades elastin.

α-1-antitrypsin

Protease inhibitor in plasma. Mostly synthesized by the liver and monocytes and the lung and macrophages.

Which enzyme regulated elastin degradation?

α-1-antitrypsin

α-1-antitrypsin deficiency

Excessive degradation of elastin.

Emphysema

Disease caused by α-1-antitrypsin deficiency in the lung.

Fibronectin

Adhesive cell surface protein that is encoded by one gene but with multiple variations due to RNA processing.

Fibronectin structure

Consists of two identical subunits that are covalently linked by disulfide bonds near the carboxyl terminal. Contains three types of repeating motifs that are organized into seven domains.

How many identical subunits in fibronectin structure?

2 (230 kD)

How are fibronectin units linked?

covalently linked by disulfide bonds near the carboxyl terminal.

Amino acids that can perform disulfide bonds

Cysteine and methionine

RGD sequence

(Arg-Gly-Asp) mediates the cell binding function of fibronectin. Acts as a binding site allowing fibronectin to bind to its receptor in the cell surface.

Integrins

Receptor for the RGD sequence. That allows the exterior of the cell to communicate with the interior.

Odontoblasts

Secrete ECM for dentin formation

DPP and DSP

Part of the ECM and are unique to dentin. They have a high affinity for calcium and regulate dentin mineralization.

DPP

Highly anionic peptide that consists of phosphoserine and aspartate or aspartic acid (Asp)

What triggers ameloblasts to secrete enamel matrix proteins?

Deposition of dentin matrix and initiation of mineralization at the dentinoenamel junction (DEJ).

How are dentin and enamel synthesized?

In opposite directions.

What type of collagen is also produced and secreted by the enamel matrix?

Collagen type I

Amelogenins

Control size and shape of crystals

Where are amelogenins secreted during enamel formation?

Into the ECM

What do amelogenins assemble into, and what charges are on their surface?

They assemble into nanospheres with anionic charges on the surface.

How do amelogenins prevent premature crystal-crystal fusion?

By electrostatic interaction, keeping a 20 nm space between forming crystals.

What happens after enzymatic removal of the charged surface of amelogenin nanospheres?

They become hydrophobic nanospheres, which interact and stabilize the growing crystals.

What happens to amelogenin fragments and water during enamel maturation?

Enzymes degrade the nanosphere, amelogenin fragments are resorbed by the cell, and water is also removed.

What is the final outcome of amelogenin regulation?

Crystals thicken and may fuse, producing mature enamel.

Laminins

Adhesive glycoprotein, helps epithelial cells bind to the underlying connective tissue. High affinity for type IV collagen.

Laminin structure

Three elongated polypeptide chains linked together forming a cruciform shape.